Toxic Epidermal Necrolysis in Patients Receiving Anticonvulsants and Cranial Irradiation: A Risk to Consider

Abstract

Toxic epidermal necrolysis (TEN) is an infrequent disease but with a high mortality rate. It is a mucocutaneous reaction resulting from hypersensitivity to a variety of agents including most anticonvulsants. Many patients with primary or metastatic intracranial tumours receive anticonvulsants for seizure prophylaxis despite their efficacy not having been clearly demonstrated. Moreover, several cases have been reported in the literature in which serious adverse drug reactions such as TEN and Stevens-Johnson syndrome (SJS) have occurred following anticonvulsants exposure. In some of these cases the effect of radiation therapy and the tapering of steroid dose on the pathogenesis of these reactions have been highlighted. We report, here, a case of TEN that appeared in a patient receiving phenytoin, and shortly after the end of cranial and thoracic irradiation therapy for brain metastases of non-small cell lung cancer. Clinical considerations about diagnosis of SJS and TEN are presented. The use of prophylactic anticonvulsants is also discussed as well as a review of the literature.

Toxic Epidermal Necrolysis after Pemetrexed and Cisplatin for Non-Small Cell Lung Cancer in a Patient with Sharp Syndrome

“…The most severe skin lesions occurred in the previous radiation field.Althoughthepatienthadnovisibleskinirritationinthe radiation field prior to the administration of pemetrexed, and the last radiation therapy had been applied 26 days before the onset of the rash, a pre-existing skin irritation may haveworsenedtheproblem.Radiation-recalldermatitisafter pemetrexedapplicationhasbeendescribedafteratimeintervalaslongas27yearsfollowingradiationtherapy [16],with attemptedexplanationssuggestingstem-celldepletionand/or mutations as well as local vascular damage causing a diminishedskinrecoverypotentialintheradiotherapyfield.Independentlyoftheuseofpemetrexed,radiotherapyortheexistenceofcancerhasbeenshowntohaveanimpactonTENincidence [13,17].Ontheotherhand,acombinationofradiationtherapywithpemetrexeduptothedoseof600mg/m 2 has beenreportedwithoutmajorskinreactioninaphaseIstudy [18],andearlysitesofcutaneousinvolvementaretypicallythe presternal region and the face [13], and may coincidentally matchwiththeradiationfieldinourpatient.…”

Irradiated fields spared Stevens-Johnson syndrome in a patient undergoing radiotherapy for bone metastases

“…6 Radiation treatment is considered by some authors to have a role in precipitating these skin reactions, interacting with the implicated drug through synergistic effects. 2,3 This point, however, is controversial: such an interaction between radiotherapy and drugs, resulting in the onset of SJS-TEN, seems, in fact, to be based more on anecdotal reports than on scientifi c reasoning. It is true that SJS-TEN can arise in patients undergoing anticonvulsant therapy and radiation treatment (especially in cases of whole-brain irradiation), but it also true that anticonvulsant exposure alone can be implicated as the cause of these severe reactions.…”

Glioma-Associated Epilepsy

“…The side effect profile of the traditional antiepileptic medications such as phenobarbital, phenytoin, carbamazepine and valproic acid was such [93,94,5,95] that it seemed often to take precedence over the desire to reduce seizure activity [96]. The administration of phenobarbital, phenytoin or primidone can markedly lower serum levels of carbamazepine and both valproic acid and lamotrigine will increase the serum concentrations of an active metabolite, carbamazepine-10,11-epoxide.…”

“…The incidence of severe rash (14%) accompanying therapy with these agents is higher in patients undergoing radiation and chemotherapy [93] and cognitive decline more pronounced [95]. Moreover, phenobarbital, phenytoin and carbamazepine are potent inducers of P450 microsomal enzymes, particularly, CYP 3A4 and CYP 2D6, and will putatively enhance metabolism of chemotherapeutic agents degraded by these enzymes resulting in the reduction of plasma levels and reduced efficacy [97,98].…”